CN116515134A - 一种体温诱导粘附性明胶基水凝胶的制备方法及应用 - Google Patents
一种体温诱导粘附性明胶基水凝胶的制备方法及应用 Download PDFInfo
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- CN116515134A CN116515134A CN202310516735.9A CN202310516735A CN116515134A CN 116515134 A CN116515134 A CN 116515134A CN 202310516735 A CN202310516735 A CN 202310516735A CN 116515134 A CN116515134 A CN 116515134A
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- sulfhydryl
- gelatin
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- body temperature
- polysaccharide
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Classifications
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- Materials For Medical Uses (AREA)
Abstract
本发明公开了一种体温诱导粘附性明胶基水凝胶的制备方法及应用，属于生物医用高分子材料技术领域。本发明的技术方案要点为：将接枝巯基的天然多糖与接枝巯基的明胶与银离子交联并负载天然活性小分子最后得到多功能水凝胶。该凝胶由双网络构建，一是银离子交联的配位网络，二是明胶的物理交联网络；其中明胶网络在体温（37℃）时组织粘附性较强，而在低温（5℃）时无组织粘附性，因此该水凝胶敷料可以按需方便移除。同时银离子赋予了该凝胶良好的抗菌性，天然活性小分子赋予了该凝胶抗炎和抗氧化性等性能；这些内在的多功能性避免了抗生素使用带来的耐药性，从而使得该水凝胶可以作为有潜力的伤口敷料应用于生物医学领域。
Description
技术领域
本发明属于生物医用高分子材料技术领域，具体涉及一种体温诱导粘附性明胶基水凝胶的制备方法及应用。
背景技术
皮肤是人体最大、最重要的器官之一，具有保护、调节和分泌等重要功能。一旦皮肤受损，会导致皮肤丧失某些重要功能，特别是损伤保护人体免受外部致病环境的屏障，迄今为止，人们已经研发出各种各样的伤口敷料。传统敷料纱布应用范围广泛，但是其在移除的过程中容易造成组织的二次损伤。在近年来开发的多种伤口敷料中，水凝胶展现出独特的优势，其可以保持伤口处的湿润，多孔结构还有利于营养物质的传输，并吸收伤口部位的渗出液等。水凝胶作为一种良好的载体，可以负载抗生素和抗炎药物等，用以实现特定功能以促进伤口愈合，但是该方法会产生耐药性等副作用，而设计制备易移除且具有内在多功能性的水凝胶伤口敷料在临床应用方面具有重要的意义。
发明内容
本发明的目的在于针对现有凝胶敷料存在的不足，提供了一种体温诱导粘附性明胶基水凝胶的制备方法及应用，该方法将接枝巯基的天然多糖和接枝巯基的明胶与银离子交联并负载天然活性小分子最后得到多功能水凝胶敷料，该水凝胶由银离子交联的配位网络以及明胶的物理交联网络构建；其中明胶网络在体温（37℃）时组织粘附性较强，而在低温（5℃）时无组织粘附性，因此该水凝胶敷料可以按需方便移除；同时银离子赋予了该水凝胶抗菌性，天然活性小分子赋予了该水凝胶抗炎和抗氧化性；内在的多功能性避免了抗生素使用带来的耐药性，从而使得该水凝胶可以作为有潜力的伤口敷料。
本发明为实现上述目的采用如下技术方案，一种体温诱导粘附性明胶基水凝胶的制备方法，其特征在于具体步骤为：
步骤S1：将巯基试剂和天然多糖溶于去离子水中，再加入催化剂，于室温反应后透析冻干得到接枝有巯基的多糖衍生物，然后将接枝有硫基的多糖衍生物溶于去离子水中得到巯基多糖溶液，其中巯基试剂为巯基乙胺、巯基乙胺盐酸盐、L-半胱胺酸或L-半胱胺酸盐酸盐中的一种或多种，天然多糖为含有羧基的天然多糖或含有氨基的天然多糖，该含有羧基的天然多糖为海藻酸钠、透明质酸钠、羧甲基纤维素、硫酸软骨素或黄原胶中的一种或多种，含有氨基的天然多糖为壳聚糖、羧甲基壳聚糖或羟乙基壳聚糖中的一种或多种，催化剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐或4-(4,6-二甲氧基三嗪)-4-甲基吗啉盐酸盐中的一种或多种；
步骤S2：将明胶溶于热的去离子水中得到明胶溶液，再加入Traut's试剂于室温搅拌混合均匀，将反应后的溶液透析冻干得到接枝有巯基的明胶，然后将接枝有巯基的明胶溶于去离子水中得到巯基明胶溶液；
步骤S3：将天然活性小分子溶于步骤S2得到的热的巯基明胶溶液中得到巯基明胶复合溶液，其中天然活性小分子为大黄酸、姜黄素、和厚朴酚、棉酚、杨梅苷、葛根素、柚皮甙、槐角苷或虎杖苷中的一种或多种；
步骤S4：将步骤S1得到的巯基多糖溶液和步骤S3得到的巯基明胶复合溶液混合均匀，再加入银离子溶液并搅拌混合均匀得到成胶前驱液，然后将成胶前驱液于室温静置即得到具有体温诱导粘附性的明胶基水凝胶。
进一步限定，步骤S1中所述含有羧基的天然多糖中的羧基或含有氨基的天然多糖中的氨基与巯基试剂的摩尔比为1:0.2~5，巯基试剂与催化剂的摩尔比为1:0.5~4，室温反应时间为12-48h，巯基多糖溶液的浓度为30~200mg/ml。
进一步限定，步骤S2中所述热的去离子水的温度为50~100℃，明胶中的氨基与Traut's试剂的摩尔比为1:0.2~5，巯基明胶溶液的浓度为50~300mg/ml。
进一步限定，步骤S3中所述热的巯基明胶溶液的温度为40~80℃，巯基明胶复合溶液中天然活性小分子的浓度为0.1~10mg/ml。
进一步限定，步骤S4中所述巯基多糖溶液与巯基明胶复合溶液的体积比为1:0.3~3，成胶前驱液中巯基和银离子的摩尔比为1:0.5~5，所得成胶前驱液于室温静置5~600min得到体温诱导粘附性明胶基水凝胶。
本发明所述的体温诱导粘附性明胶基水凝胶在制备生物医用敷料中的应用。
本发明所述的体温诱导粘附性明胶基水凝胶材料在制备促进创伤愈合水凝胶伤口敷料中的应用。
本发明与现有技术相比具有以下优点和有益效果：本发明提供的体温诱导粘附性明胶基水凝胶包含生物相容性良好的天然多糖和明胶，以及提供优良抗菌性能的银离子和促进伤口愈合的天然活性小分子，具有温度依赖的粘附性，避免了传统水凝胶敷料移除时易造成组织的二次损伤的缺点，以及抗生素和抗炎等药物使用所带来的耐药性缺点，为促进创面愈合提供了一种新型敷料。
附图说明
图1是本发明实施例1制备的水凝胶冻干后的扫描电子显微镜图；
图2是本发明实施例1制备的水凝胶的抗菌性能测试结果；
图3是本发明实施例1制备的水凝胶的可逆粘附性测试结果；
图4是本发明实施例1制备的水凝胶在小鼠皮肤全层伤口实验第14天时伤口组织的HE染色图。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
步骤S1：将0.50g透明质酸钠和0.28g巯基乙胺盐酸盐溶于50ml去离子水中，然后加入0.48g催化剂1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，于室温搅拌反应12h，反应液在去离子水中透析3天后冻干得到接枝有巯基的透明质酸钠，最后将接枝有巯基的透明质酸钠溶于去离子水中得到浓度为50mg/ml的巯基透明质酸钠溶液；
步骤S2：将1.0g明胶溶于100ml60℃去离子水中，加入50mgTraut's试剂并于室温搅拌反应12h，反应液在去离子水中透析3天后冻干得到接枝有巯基乙胺的明胶，最后将接枝有巯基乙胺的明胶溶于60℃去离子水中得到浓度为200mg/ml的巯基明胶溶液；
步骤S3：将10mg大黄酸溶于步骤S2中得到的1ml 60℃巯基明胶溶液中得到巯基明胶复合溶液；
步骤S4：将0.5ml步骤S1所得巯基透明质酸钠溶液与0.5ml步骤S3所得巯基明胶复合溶液充分混合后加入150μl浓度为0.1mmol/L的银离子溶液，混匀后得到的成胶前驱液于室温静置30min即得到具有体温诱导粘附性的明胶基水凝胶。
实施例2
步骤S1：将0.44g羟乙基壳聚糖和0.24gL-半胱氨酸溶于150ml去离子水中，然后加入0.38g催化剂1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，于室温搅拌反应24h，反应液在去离子水中透析3天后冻干得到接枝有巯基的羟乙基壳聚糖，最后将得到的接枝有巯基的羟乙基壳聚糖溶于去离子水中得到浓度为20mg/ml的巯基化羟乙基壳聚糖溶液；
步骤S2：将1.0g明胶溶于100ml60℃去离子水中，加入100mgTraut's试剂后并于室温搅拌反应18h，反应液在去离子水中透析3天后冻干得到接枝有巯基乙胺的明胶，最后将接枝有巯基乙胺的明胶溶于60℃去离子水中得到浓度为150mg/ml的巯基明胶溶液；
步骤S3：将8mg葛根素溶于步骤S2中得到的1ml 60℃巯基明胶溶液中得到巯基明胶复合溶液；
步骤S4：将0.4ml步骤S1巯基化羟乙基壳聚糖溶液与0.6ml步骤S3所得巯基明胶复合溶液充分混合后加入200μl浓度为0.1mmol/L的银离子溶液，混匀后得到的成胶前驱液于室温静置20min即得到具有体温诱导粘附性的明胶基水凝胶。
为了说明本发明的水凝胶的各项性能，对实施例1制备的体温诱导粘附性明胶基水凝胶进行了测试，测试结果见图1～4。
图1为实施例1制备的水凝胶冻干后的扫描电子显微镜图，可以观察到三维网状凝胶骨架结构。
图2为实施例1制备的水凝胶的抗菌性能测试结果，如图所示，相对于空白组，制备的水凝胶对革兰氏阴性的大肠杆菌和革兰氏阳性的金黄色葡萄球菌展现出良好的抗菌性能。
图3为实施例1制备的水凝胶可逆粘附性测试结果，如图所示，该水凝胶在体温时具有较强的组织（猪皮）粘附性，而在低温时粘附性为零，使得该水凝胶具有无创可移除性。
图4为实施例1制备的水凝胶在小鼠皮肤全层伤口实验第14天时伤口组织的HE染色图，相对于空白组不完整的新生组织，制备的水凝胶组中新生皮肤组织完整，具有明显的毛孔等皮肤附属器官，证明了所制备的水凝胶具有良好的促进伤口愈合的性能。
综上，本发明提供的体温诱导粘附性明胶基水凝胶展现出良好的抗菌、促愈合等性能；通过小鼠皮肤全层伤口实验，验证了该水凝胶能够促进较为完整的皮肤组织及其附属器官再生从而加速伤口的愈合。
以上显示和描述了本发明的基本原理、主要特征和优点，在不脱离本发明精神和范围的前提下，本发明还有各种变化和改进，这些变化和改进都要求落入本发明的保护范围之内。
Claims (7)
1.一种体温诱导粘附性明胶基水凝胶的制备方法，其特征在于具体步骤为：
步骤S1：将巯基试剂和天然多糖溶于去离子水中，再加入催化剂，于室温反应后透析冻干得到接枝有巯基的多糖衍生物，然后将接枝有硫基的多糖衍生物溶于去离子水中得到巯基多糖溶液，其中巯基试剂为巯基乙胺、巯基乙胺盐酸盐、L-半胱胺酸或L-半胱胺酸盐酸盐中的一种或多种，天然多糖为含有羧基的天然多糖或含有氨基的天然多糖，该含有羧基的天然多糖为海藻酸钠、透明质酸钠、羧甲基纤维素、硫酸软骨素或黄原胶中的一种或多种，含有氨基的天然多糖为壳聚糖、羧甲基壳聚糖或羟乙基壳聚糖中的一种或多种，催化剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐或4-(4,6-二甲氧基三嗪)-4-甲基吗啉盐酸盐中的一种或多种；
步骤S2：将明胶溶于热的去离子水中得到明胶溶液，再加入Traut's试剂于室温搅拌混合均匀，将反应后的溶液透析冻干得到接枝有巯基的明胶，然后将接枝有巯基的明胶溶于去离子水中得到巯基明胶溶液；
步骤S3：将天然活性小分子溶于步骤S2得到的热的巯基明胶溶液中得到巯基明胶复合溶液，其中天然活性小分子为大黄酸、姜黄素、和厚朴酚、棉酚、杨梅苷、葛根素、柚皮甙、槐角苷或虎杖苷中的一种或多种；
步骤S4：将步骤S1得到的巯基多糖溶液和步骤S3得到的巯基明胶复合溶液混合均匀，再加入银离子溶液并搅拌混合均匀得到成胶前驱液，然后将成胶前驱液于室温静置即得到具有体温诱导粘附性的明胶基水凝胶。
2.根据权利要求1所述的体温诱导粘附性明胶基水凝胶的制备方法，其特征在于：步骤S1中所述含有羧基的天然多糖中的羧基或含有氨基的天然多糖中的氨基与巯基试剂的摩尔比为1:0.2~5，巯基试剂与催化剂的摩尔比为1:0.5~4，室温反应时间为12-48h，巯基多糖溶液的浓度为30~200mg/ml。
3.根据权利要求1所述的体温诱导粘附性明胶基水凝胶的制备方法，其特征在于：步骤S2中所述热的去离子水的温度为50~100℃，明胶中的氨基与Traut's试剂的摩尔比为1:0.2~5，巯基明胶溶液的浓度为50~300mg/ml。
4.根据权利要求1所述的体温诱导粘附性明胶基水凝胶的制备方法，其特征在于：步骤S3中所述热的巯基明胶溶液的温度为40~80℃，巯基明胶复合溶液中天然活性小分子的浓度为0.1~10mg/ml。
5.根据权利要求1所述的体温诱导粘附性明胶基水凝胶的制备方法，其特征在于：步骤S4中所述巯基多糖溶液与巯基明胶复合溶液的体积比为1:0.3~3，成胶前驱液中巯基和银离子的摩尔比为1:0.5~5，所得成胶前驱液于室温静置5~600min得到体温诱导粘附性明胶基水凝胶。
6.根据权利要求1~5所述的方法制备的体温诱导粘附性明胶基水凝胶在制备生物医用敷料中的应用。
7.根据权利要求1~5所述的方法制备的体温诱导粘附性明胶基水凝胶在制备促进创伤愈合水凝胶伤口敷料中的应用。
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